Corticosteroids, Intracranial Pressure and the Pathogenesis of Idiopathic Intracranial Hypertension.

Idiopathic intracranial hypertension, (IIH), is a common blinding condition in overweight women. Affected patients suffer with severe headaches and significant visual loss resulting from increased brain pressure, called intracranial pressure. The cause of raised brain pressure in IIH is not known, but it is likely to relate to abnormalities in the balance between production and drainage of brain fluid, known as cerebrospinal fluid (CSF). As greater than 90% of IIH patients are female and obese we expect that the disordered CSF balance may relate to hormones and obesity, our study will investigate this further. Initially, we will identify where and how these hormones act in the areas of the brain that are known to produce and drain CSF. We will then study the urine, serum and CSF of patients with IIH to determine which hormones and chemicals are unique to the disease. Finally, weight loss has previously been suggested as a treatment for IIH, but to date this has not been proven. A clinical study will be carried out to identify whether weight loss is truly effective in treating IIH, and if so whether this works by altering disease specific hormone levels.

Idiopathic intracranial hypertension, (IIH), is a common blinding condition of unknown aetiology amongst the young obese female population (20 per 100,000). It is likely the incidence will rise further with the global obesity epidemic. IIH is characterised by elevated intracranial pressure (ICP) which manifests as disabling headaches and severe visual loss secondary to optic nerve compression. Based on our work in the related ocular ciliary epithelium, and also the link between IIH and obesity, I propose a role for corticosteroids and their pre-receptor regulator, the enzyme 11?-Hydroxysteroid dehydrogenase, in the pathogenesis of the raised ICP. Importantly, treatment protocols for IIH are not established. In fact, a recent Cochrane Review concluded that there was inadequate information regarding causation and which treatments were considered beneficial and which were potentially harmful. I aim to develop a novel therapeutic target for patients with IIH, and provide an evidence base for the use of weight loss regimens in affected cases.

The objectives of my proposal are to:

1. Perform in vitro studies to characterise the role of corticosteroids and their metabolic pathways in CSF production by the choroid plexus and drainage through the arachnoid granulation tissue.

2. Conduct in vivo studies in patients with IIH to define the function of the hypothalamo-pituitary-adrenal axis, cortisol metabolism and CSF steroid levels.

3. Undertake a detailed clinical interventional study that will evaluate whether a carefully monitored and previously validated weight loss program is effective in reducing ICP and treating IIH. If so, address why weight loss may be beneficial by monitoring for changes in the levels of corticosteroids and related metabolites.

Unravelling the role of corticosteroids and particularly their metabolism by enzymes such as 11?-hydroxysteroid dehydrogenase (11?-HSD), may have major ramifications for patients with IIH. In addition to weight loss, selective inhibitors of 11?-HSD that may reduce local CSF steroid hormone production are under development. The translational component of this work offers potentially exciting therapies for the treatment of IIH.